Avid readers of dramatic novels from yesteryear will recall stories from thedays when fevered patients were watched over by family, and the oldies inthe group just “knew” that a proper fever would “break” with a sweat. When thathappened, they knew that the prognosis would be good. Of course, such sentimentstoday would be greeted with alarm, or scepticism, by those who consider illnessshould never be endured.

Isn’t that why acetaminophen (in all their different brand names) is reachedfor, at the first sign of a fever?

In 2001, a headline

1made me look twice. “Sweat has the power to fight offdisease.”We were told that sweat contains a versatile antibiotic that may be onthe front line against disease-causing bacteria and that: “The researchers saiddermcidin probably plays a key role in the innate immune responses of the skin”.A news roundup from the British Medical Journal told us2that dermcidin killedescherichia coli, enterococcus faecalis, staphylococcus aureusand Candidaalbicans. It was active at high salt concentrations and the acidity range of humansweat. In concentrations of 1–10 μg/ml, it killed all of the staph aureuscoloniesin only four hours. Unsurprisingly, the scientists didn’t know how dermcidinworked.

Up until the late 1990s the skin was simply thought to be a “barrier” with noactive participation in the immune system. The original 2001 paper

As time has gone on, other researchers have taken a closer look at skin, and havefound that the neutrophil,

4 which is the professional phagocyte of fundamentalimportance for defence against micro-organisms, provides instant help, not onlyin microbial infection,5but to the growth factors when the skin is broken and thereis a risk of infection. Another article6 says that mast cells, macrophages and skincells produce antimicrobial peptides. These are called cathelicidin, which disruptsbacterial cell walls, modifies the host cells inflammation, and provides additionalimmune defence. At the heart of this all, is our friendly neutrophil:

The article looked at whether just skin and mast cells were involved, or whetherneutrophils were also important. Using mice, they found that mice with fewneutrophils developed much worse tissue death (necrosis) and had 3,000 timesthe amount of bacteria on the skin than mice with active neutrophils. The skincells worked hard and could produce some cathelicidin on their own, but didn’thave the killing power of the skin cells plus neutrophils. The article’s conclusionsaid that life-threatening necrotizing skin and soft-tissue infections can develop inpatients with depressed neutrophils, but that numerous examples exist of patientswith increased frequency of skin infections who have no

Properly fed, healthy children, whose parents know what to do, and what notto do, will rarely get any complications to chickenpox. As was the case for ourchildren, well-managed chickenpox should not even lead to any scarring. Solet’s ask some questions here, with chickenpox in mind. What is the function offever?

Here’s a really simple statement11 from twenty years ago: “… elevated body temperatureenhances the infl ammatory response and function of the immune systemat the same time that it reduces the replication of microbes and tumor cells.”

Not so simple is this sentence.

“Fever also appears to be a prominent componentof cytokine therapy and attends the use of several biologic response modifiers.”

Fever switches on the chemical messengers and processes which call on the bodyimmune system to respond and “modify” or deal with the infection.

If fever is a key to an immune-system process, without a fever, how effective isthe body going to be in fi ghting viruses, or bacteria? With viruses like chickenpox,which are known to have an affinity with

group A streptococcus,

which can infectthe pox rash and so have access to the body, what do we want the immune systemto do? It’s pretty obvious isn’t it?

We

want

to allow the body temperature to rise to the level it needs so that allthe on-switches can be thrown.

We

want

the body to send out all those little chemical messengers which getthe antiviral side of things going.

We

wantthe messengers to call the neutrophils to join the skin cells in producingcathelicidin, and to work with the whole array of anti-viral and antibacterialcomponents12in “sweat” to stop group A streptococcus

in its tracks.

As a 1991 article13 says: “… temperature elevation … enhances the processesinvolved in initial antigen recognition and support for immunological specifi cresponse to challenge.”

We want the body to recognize the virus, ring the bell and sound the red alert(fever) to fight, don’t we? Why, then, turn the fever off with acetaminophenproducts? Doesn’t that defy logic?

A 1998 article16 said: “The elevation of body temperature by a few degrees mayimprove the efficiency of macrophages in killing invading bacteria, whereas itimpairs the replication of many microorganisms, giving the immune system anadaptive advantage. There is a simultaneous switch from the burning of glucose,an excellent substrate for bacterial growth, to metabolism based on proteolysisand lipolysis. The host organism is anorectic (doesn’t want to eat) minimizingthe availability of glucose, and somnolent, reducing the demand by musclesfor energy substrate. During the febrile response, the liver produced proteinsknown as acute phase reactants … the net effect … is to give the host organisman adaptive advantage over the invader.” (Underlining mine.)

…

Treating fevers is dicing with more severe infection, and a greater likelihood ofdeath, because fever is a key immune response to get the immune system workingproperly.

You mess with fever, and you mess with lots of things. It stands to reason. Doyou need to know what the medical profession does not yet know about fever inits totality, to see that?

Back to chickenpox. Tucked away in a small co

rner of the New Zealand Heraldin 2001 was a warning:17 “GPs warned over chickenpox drug.” Doctors werewarned about treating chickenpox with ibuprofen to reduce fever because of ahigher rate of necrotizing fasciitis18. There was no mention of paracetamol in thewarning, yet, since both perform the same function, there is reason to argue thatparacetamol might do the same as ibuprofen. In USA, the link between the use ofnon-steroidal anti-infl ammatories and chickenpox reached the ears of doctors,19,20

but not, it seems, the public.

There was a flurry of articles suggesting it was dangerous to use anti-febriledrugs with chickenpox; there was also an article by a group of doctors, who indefiance of all logic and known immunological impacts of drugs used to reducefever, decided that there was no association. They

decreed that when parents useddrugs to “treat high fever and severe illness”, drug use was merely the identifyingfactor of who was at high risk for secondary bacterial infection! That interestinglittle word “coincidental” again.

… I see the increase in these infections as evidence of a total lack of commonsense about how to prevent complications. I see the association between nonsteroidalanti-febrile drugs and GAS as a predictable outcome of the loss ofhome nursing skills and handed-down generational wisdom. I see the increase insecondary bacterial infections as something which can stem from parental lack ofunderstanding that messing around with fever, and using symptom-suppressing/immune-suppressing drugs can restrict the ability of the immune system tofi ght the virus. It also reduces the ability of the leucocyte system of neutrophils,macrophages and phagocytes to fight bacterial toxins from secondary bacterialinfections.

As pointed out in Chapter 70, if you don’t have enough vitamin C in yoursystem, then the neutrophils won’t be recognized by the macrophages, and youmight be in big trouble, because if that happens, the result could be toxic shock/sepsis taking hold very quickly. Even if you have enough vitamin C, if the amountof GAS toxin is such that the glucose transporters (which are part of the vitamin Cshuttle service which takes ascorbate from A to B) are blocked, that can result in aGAS infection which threatens to run out of control. The quickest way to restorethe immune function in a case of sepsis is by giving vitamin C intravenously. Thebody can fight sepsis by itself, but it’s a bit more of a lottery as to whether it willsucceed if it doesn’t have the tools to do the job.

BERLIN — October 8, 2008 — The reported use of paracetamol (acetaminophen) in the first year of life is associated with increases in reported symptoms of asthma and risk of severe asthma symptoms in children aged 6 to 7 years, according to analysis of data from the multicentre, multicountry, cross-sectional International Study of Asthma and Allergies in Children (ISAAC).

The study also found an association between use of paracetamol in childhood and an increased risk of symptoms of rhinoconjunctivitis and eczema in childhood, said principal investigator Richard Beasley, MD, Medical Research Institute of New Zealand, Wellington, New Zealand.

The increased international use of paracetamol over the last 40 years occurred contemporaneously with an increased prevalence of asthma, Dr. Beasley said during a presentation on October 7 at the European Respiratory Society (ERS) 18th Annual Congress.

“[This study] was based on a hypothesis that was raised 10 years ago, where it was proposed that the switch from aspirin to paracetamol in childhood may have contributed to the increase in asthma prevalence that was noted in many countries in the 1980s,” he said.

Therefore, Dr. Beasley and colleagues conducted a study to investigate the association between paracetamol use in infancy and self-reported symptoms of asthma in children aged 6 to 7 years participating in the ISAAC program, which was formed in 1991 to facilitate research into asthma, allergic rhinitis, and eczema.

Data were obtained from 2 groups (children aged 6 to 7 and 13 to 14) from random samples of schools in defined geographical areas worldwide. Samples were collected using 2 simple standardised questionnaires that were completed by the children’s parents or guardians.

The prevalence questionnaire obtained data regarding symptoms of asthma, rhinoconjunctivitis, and eczema in these children, while the environmental questionnaire obtained data on a wide range of putative protective and risk factors for asthma and allergic disorders, including paracetamol use for fever in the first year of life.

A total of 194,555 children from 69 centres in 29 countries were included in the analysis, with the multivariate analysis based on 105,041 of these children with complete covariance data.

When severe asthma symptoms were defined as wheezing causing sleep disturbance or limiting speech, or 4 or more attacks of wheezing in the past 12 months, a similar significant association was seen at the multivariate level for the use of paracetamol (OR, 1.43; 95% CI, 1.30-1.58).

Dr. Beasley noted, “While paracetamol has been shown to be safer than the alternatives and is the recommended treatment … what we found in this study was that there was a very widespread use of paracetamol beyond its indication for relief of high fever.”

Indeed, as he stressed, “What we need now is randomised controlled trials to really sort this out properly, and from these trials, there will be the basis for making firm guidelines in terms of management.”

The study was published in The Lancet in September 2008 (Beasley R et al. 2008;372:1039-1048).

The Food and Drug Administration will rewrite decades-old federal regulations governing how over-the-counter cold and cough medicines are marketed to children amid concerns over whether the products are safe and effective.

The FDA is revisiting marketing rules.

As part of that effort the agency held a daylong hearing Thursday to solicit views about how the rules should be changed. While the effort is expected to take years, the end result could be a tougher regulatory environment for many over-the-counter cold and cough products — such as requiring drug makers to seek approval for their products in a manner similar to that for prescription drugs.

An estimated 95 million packages of children’s over-the-counter cold and cough medicines are sold each year in the U.S. under a range of brand names, including Johnson & Johnson‘s Tylenol Plus Cold, Novartis AG’s Triaminic and Wyeth’s Robitussin, according to industry estimates.

John Jenkins, the FDA’s office of new drugs director, said the system that currently governs over-the-counter cold and cough products was really designed to grandfather the over-the-counter medicines that were on the market in the 1960s. The system allowed certain active ingredients (such as those in decongestants) to be legally marketed without obtaining prior FDA approval for each individual product. The studies used to establish the safety of those ingredients were mostly done in adults; current dosing recommendations for kids are simply reduced from adult doses.

Antibiotics cause a stall out or dying off of intestinal flora, which kills the e.coli in the gut. When killed, the endotoxin located in the e.coli’s outer coating is released, which often causes a cascade of health issues to result. Endotoxemia affects the glutathione biochemical pathways, which are also a key component of the immune system, among other vital functions.

“Antibiotics disrupt the normal population of beneficial microbes/bacteria in the gastrointestinal tract of all Human/animals. These beneficial bacteria are the first fine of defense against most diseases, without them the Human/animal is more susceptible to other infections. Antibiotics depress the immune system by decreasing the number of circulating white blood cells. This lowers the Human/animal’s ability to fight infections. Some antibiotics, such as chloramphenicol, can cause irreversible damage to the bone marrow. Many bacteria develop resistance to the effects of antibiotics. This resistance can be passed to other bacteria, The concern is that if humans are exposed to resistant bacteria then the use of antibiotics may be ineffective in treating any resulting disease.” – Richard J. Holliday, DVM

Antipyretics, also known as fever reducers, lower the immune system which can set babies and children up for potentially worse problems.

Paracetamol (fever reducer) may prolong infection and reduce the antibody response in mild disease, and increase morbidity and mortality (death) in severe infection.

If you can get rid of the vaccine pyrogens that are causing the temperature, it will come down on its own, and the quickest way to do that is vitamin C (sodium ascorbate). Diarrhea is a sign of gut dysbiosis and is a sign there is a significant immunological disturbance in the body. 70% of the immune system is located in the gut, and if you mess with that, the gut allows vital immunological resources to work elsewhere. Foul smelling diapers are also a very common with vaccine reaction. It’s the most obvious indicator that the body is going haywire.

The findings were presented here at the annual meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI).

So what could be happening? While no one knows for sure, Perzanowski says that acetaminophen use may deplete the lung of an antioxidant called glutathione. Researchers think glutathione, which is found in the lining of airways, may play an important role in preventing damage to the lungs.

Fever is often a beneficial host response to infection, and moderate fever improves immunity. Therefore, it may not be a good idea to give drugs that reduce temperature to patients with severe infection. I have recently reviewed 1 the results of 9 controlled trials in mammals of the effect of paracetamol or aspirin on mortality or virus excretion. Four trials found that aspirin increased mortality in bacterial or viral infection. Viral shedding was increased by paracetamol or aspirin in 3 studies, possibly increased in one, and not affected in two (one used only pharyngeal washings, and one had only 9 subjects in the aspirin and placebo groups). One study found that antibody production was impaired by both paracetamol and aspirin, but no effect on antibody production was detected in the study with only 9 subjects in the aspirin and placebo groups. This evidence suggests that aspirin and paracetamol increase mortality in severe infection, and that they may prolong the infection and reduce the antibody response in mild disease.
….It should be explained to parents that fever is usually a helpful response to infection, and that paracetamol should be used to reduce discomfort, but not to treat fever.

“The elevation of body temperature by a few degrees may improve the efficiency of macrophages in killing invading bacteria, whereas it (fever) impairs the replication of many microorganisms, giving the immune system an adaptive advantage.

There is a simultaneous switch from the burning of glucose, an excellent substrate for bacterial growth, to metabolism based on proteolysis and lipolysis. The host organism also becomes anorexic, which minimizes the availability of glucose, and somnolent, which reduces the demand by muscles for energy substrate. During the febrile response, the liver produces proteins known as acute-phase reactants. Some of these proteins bind divalent cations, which are necessary for the proliferation of many microorganisms.

The net effect of the metabolic responses activated during fever is to give the host organism an adaptive advantage over the invader.”

“Antipyretic drugs are effective in diminishing fever, but they have significant side effects and may suppress signs of ongoing infection.”

“Antipyretic therapy should not be instituted routinely for every febrile episode but should be based on evaluation of relative risks in the individual case and reassessed if anticipated benefits are not achieved.”

Pg 1594: “The decision to administer antipyretics is frequently made without a documented rational. Current understanding of the mechanisms and pathogenesis of fever suggests that the febrile process has a role in host defense and that routine antipyretic therapy for fever is generally unnecessary and conceivably harmful. ”

“Decisions to attempt suppression of fever should be based in infrequent indications arising in an individual case and should take into account the potential risks of antipyresis as well as its often questionable benefits.”

Pg 1594: “In the vast majority of febrile illnesses, there is no evidence that fever is detrimental or that antipyretic therapy offers any significant benefit. Indeed, the limited information available on in vitro immune functions and in vivo outcomes would suggest that fever usually does more good than harm.”

“In treating fever “symptomatically” one should not lose sight of the fact that elevated temperatures, whatever their physiologic function, do serve as a signal both to the patient and to the caregiver. Nonspecific suppression of fever may deprive one of clues to a need for further diagnostic investigation, or for changes in therapy. Although these clues will often occur in the context of antipyretic use, one study has indicated that patients with a variety of bacterial infections receiving antipyretics experience a significant delay in institution of needed antibiotic changes.”

Page 31: “antipyretics are among the most widely used pharmacologic agents. Traditional rationales for their use include relief of discomfort associated with fever, prevention of febrile seizures, avoidance of the high metabolic costs of fever in those who are malnourished or who have cardiac or pulmonary disease, and lessening of brain edema in central nervous system disease or trauma. However, accumulating evidence indicates that fever may be an important defense mechanism.”

“The objective of this study was to determine whether paracetamol (acetaminophen) affects the outcome of children with fever due to bacterial infectious disease….. the data suggest that frequent administration of antipyretics to children with infectious disease may lead to a worsening of their illness.”

“The most commonly used antipyretic drugs are acetylsalicylic acid (ASA) paracetamol (acetaminophen) and dipyrone (metamizol). …Paracetamol is the most common cause of acute hepatic failure… in the light of these findings, the extensive use of antipyretics drugs has been seriously questioned.”

“Page 398: “Paracetamol has a pronounced liver toxicity. In the United Kingdom paracetamol is considered to be responsible for more cases of acute hepatic failure than any other cause.”

Page 399 “the potential for toxicity of ASA and paracetamol, the two most extensively used antipyretics in the febrile child, underlines the constraints within which treatment decisions have to be made. The fact that both drugs are sold as “over the counter” products, while the medication of child fever often occurs without medical control, should be a matter of concern.

Result: An increase of mortality with absence of fever in pneumococcal meningitis.

“In summary, what does the evidence seem to indicate? Fever represents a universal, ancient, and usually beneficial response to infection, and its suppression under most circumstances has few, if any, demonstrable benefits. On the other hand, some harmful effects have been shown to occur as a result of suppressing fever: in most individuals, these are slight, but when translated to millions of people, they may result in an increase in morbidity and perhaps the occurrence of occasional mortality. It is clear, therefore, that widespread use of antipyretics should not be encouraged either in developing countries or in industrial societies.”

Chickenpox treated with Tylenol/Ibuprofen provokes bacterial skin infections into fulminant necrotising fasciitis. This happens by prolonging inflammation and down regulating the immune system. It can no longer fully activate the adaptive arm of immunity either.

The authors recently observed that frequent paracetamol use was positively associated with asthma and rhinitis in young adults. ….Their associations with national 1994/1995 per capita paracetamol sales were measured using linear regression. Paracetamol sales were high in English-speaking countries, and were positively associated with asthma symptoms, eczema and allergic rhinoconjunctivitis in 13-14-yr-olds, and with wheeze, diagnosed asthma, rhinitis and bronchial responsiveness in adults. The prevalence of wheeze increased by 0.52% in 13-14-yr-olds and by 0.26% in adults (p<0.0005) for each gram increase in per capita paracetamol sales. These ecological findings require cautious interpretation, but raise the possibility that variation in paracetamol usage may explain some of the variation in atopic disease prevalence between countries.

“However, the risk of an outpatient visit for asthma was significantly lower in the ibuprofen group; compared with children who were randomized to acetaminophen, the relative risk for children who were assigned to ibuprofen was 0.56 (95% confidence interval: 0.34-0.95). CONCLUSIONS: Rather than supporting the hypothesis that ibuprofen increases asthma morbidity among children who are not known to be sensitive to aspirin or other nonsteroidal antiinflammatory drugs, these data suggest that compared with acetaminophen, ibuprofen may reduce such risks. Whether the observed difference in morbidity according to treatment group is attributable to increased risk after acetaminophen use or a decrease after ibuprofen cannot be determined.”

In addition to the probability that antipyretics may prolong the course of mild to moderate infectious illnesses, what other deleterious effects might they have? Russell et al. point out that little is known about the pharmacokinetics of these drugs in poorly or malnourished children. Even in developed countries, all available methods of antipyresis must be treated with respect. Warning labels became required for paracetamol recently and for aspirin in the more distant past. In addition to acute poisoning, the former has been implicated in the development of chronic renal disease, and perhaps liver failure, when repeatedly administered over prolonged periods of time . Perhaps more important is the fact that antipyretics mask symptoms or signs; children with pneumonia, for example, may not receive a proper diagnosis because their respiratory rate decreases (4) or because, when the body temperature starts to fall, the child may be considered to be on the way to recovery and thus needing no further observation. Finally, of course, the costs may consume a significant amount of resources that, in developing countries, could be better devoted to specific diagnosis and therapy.

Other potential benefits of reducing fever are sometimes cited to justify the use of antipyresis. A common assumption is that these drugs make patients feel better, but no clear evidence shows that this is so. Parents and physicians consistently cannot distinguish between the effects of placebo and paracetamol in most circumstances. Perhaps the exceptions are conditions accompanied by pain, for which the analgesic effects of the medication provide the benefit. When fevers rise above 39.5 oC, a reduction in body temperature is sometimes accompanied by an improvement in subjective symptoms, but this is inconstant, with young children seeming to benefit more than older children.

The major problem when evaluating the subjective effects of antipyretics is that they have an enormous placebo value – as various studies have shown. Despite the firm belief in the effects of antipyretics, children do not feel any better, eat better, or become more active after their use than they do after they receive placebo. The argument that the use of antipyretics reduces the occurrence of febrile seizures also is not based on evidence: no studies have shown this to be true. Even in children with previous febrile seizures, the use of antipyretics has not been helpful. Some physicians believe that the response to antipyretics can be used to differentiate between bacterial and viral infections, with the latter responding more completely and promptly. Numerous studies have shown this to be a fallacy.

Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than 1 billion US dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever?

FDA fails to reduce accessibility of paracetamol despite 450 deaths a year. Confidential documents from the US Food and Drug Administration suggest that the agency has avoided a debate on tough new measures to reduce overdoses from painkillers to avoid offending the pharmaceutical industry. Ray Moynihan reports from Washington, DC

” A confidential draft document reveals that the Office of Drug Safety also wanted the advisory panel to discuss whether the “maximum tablet strength should be decreased,” whether “combination products be reformulated without acetaminophen,” and whether there was “a need to standardize the various paediatric formulations.”

The advisers never saw that draft, however, and none of these key options ended up being clearly presented to the committee by the FDA in the final list of questions they were to consider.

…. “The committee would have preferred more focused questions,” he said.

According to one FDA insider, the draft questions were dropped because senior FDA managers saw them as too offensive to Johnson & Johnson. Asked about this alleged corporate influence within the FDA, Dr Cantilena smiled and said he did not want to speculate.

“The elevation of body temperature by a few degrees may improve the efficiency of macrophages in killing invading bacteria, whereas it (fever) impairs the replication of many microorganisms, giving the immune system an adaptive advantage.

There is a simultaneous switch from the burning of glucose, an excellent substrate for bacterial growth, to metabolism based on proteolysis and lipolysis. The host organism also becomes anorexic, which minimizes the availability of glucose, and somnolent, which reduces the demand by muscles for energy substrate. During the febrile response, the liver produces proteins known as acute-phase reactants. Some of these proteins bind divalent cations, which are necessary for the proliferation of many microorganisms.

The net effect of the metabolic responses activated during fever is to give the host organism an adaptive advantage over the invader.”

“in patients without heart and lung disease fever is harmful only at temperatures over 41 o C; such high termperatures are usually caused by heat stroke or brain injury, and they do not respond to paracetamol or aspirin.” There is no evidence that antipyretics prevent febrile convulsions”

“The most commonly used antipyretic drugs are acetylsalicylic acid (ASA) paracetamol (acetaminophen) and dipyrone (metamizol). …Paracetamol is the most common cause of acute hepatic failure… in the light of these findings, the extensive use of antipyretics drugs has been seriously questioned.”

“Page 398: “Paracetamol has a pronounced liver toxicity. In the United Kingdom paracetamol is considered to be responsible for more cases of acute hepatic failure than any other cause.”

Page 399 “the potential for toxicity of ASA and paracetamol, the two most extensively used antipyretics in the febrile child, underlines the constraints within which treatment decisions have to be made. The fact that both drugs are sold as “over the counter” products, while the medication of child fever often occurs without medical control, should be a matter of concern.

Antipyretics appear to prolong illness by reducing the temperature, thereby disabling the body’s full ability to deal with whatever is the problem. In a nutshell, the lower the temperature, the longer the duration of illness. The higher the temperature, the shorter duration of illness. Immunologically, temperatures from infection are specifically designed to speed up and kick the immune system into gear, release cytokines and other immunological forces to deal with the problem.